Therapeutic application of alpha-1-antitrypsin in COVID-19

Ritzmann, F.; Chitirala, P.; Yao, Y.; Krueger, N.; Hoffmann, M.; Zuo, W.; Lammert, F.; Smola, S.; Seiwert, N.; Tov, N.; Alagem, N.; Mozafari, B.; Guenther, K.; Seibert, M.; Hoersch, S.; Volk, T.; Lepper, P. M.; Danziger, G.; Poehlmann, S.; Beisswenger, C.; Herr, C.; Bals, R.

Rationale: The treatment options for COVID-19 patients are sparse and do not show sufficient efficacy. Alpha-1-antitrypsin (AAT) is a multi-functional host-defense protein with anti-proteolytic and anti-inflammatory activities. Objectives: The aim of the present study was to evaluate whether AAT is a suitable candidate for treatment of COVID-19. Methods: AAT and inflammatory markers were measured in the serum of COVID-19 patients. Human cell cultures were employed to determine the cell-based anti-protease activity of AAT and to test whether AAT inhibits the host cell entry of vesicular stomatitis virus (VSV) particles bearing the spike (S) protein of SARS-CoV-2 and the replication of authentic SARS-CoV-2. Inhaled and / or intravenous AAT was applied to nine patients with mild-to-moderate COVID-19. Measurements and Main Results: The serum AAT concentration in COVID-19 patients was increased as compared to control patients. The relative AAT concentrations were decreased in severe COVID-19 or in non-survivors in ratio to inflammatory blood biomarkers. AAT inhibited serine protease activity in human cell cultures, the uptake of VSV-S into airway cell lines and the replication of SARS-CoV-2 in human lung organoids. All patients, who received AAT, survived and showed decreasing respiratory distress, inflammatory markers, and viral load. Conclusion: AAT has anti-SARS-CoV-2 activity in human cell models, is well tolerated in patients with COVID-19 and together with its anti-inflammatory properties might be a good candidate for treatment of COVID-19.